Systems and methods for lymph node and vessel imaging

ABSTRACT

This disclosure provides a method for imaging lymph nodes and lymphatic vessels without a contrast agent. The method includes providing, using an optical source, an infrared illumination to a region of a subject having at least one lymphatic component, detecting a reflected portion of the infrared illumination directly reflected from the region using a sensor positioned thereabout, and generating at least one image indicative of the at least one lymphatic component in the subject using the reflected portion of the infrared illumination.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/781,338, filed Feb. 4, 2020, which claims priority to U.S.Provisional Application No. 62/848,178, filed May 15, 2019, and to U.S.Provisional Application No. 62/800,674, filed Feb. 4, 2019, which arehereby incorporated by reference herein in their entirety for allpurposes.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under P30 CA014051awarded by the National Institutes of Health. The government has certainrights in the invention.

BACKGROUND

Lymph nodes, also known as lymph glands, are oval-shaped organs that arewidely present throughout the human and animal bodies. Lymph node is anintegral part of the lymphatic system, which is responsible for theimmune responses to protect the body from diseases and infections. Thecondition of lymph nodes can be directly indicative to one's healthconditions. Swollen lymph nodes can be an indication of bacterialinfection, virus infection, cancer, etc. Checking the condition of lymphnodes by imaging them is extremely useful to disease diagnosis,prevention, and treatment.

Currently, there are a number of imaging modalities to visualize andexamine the lymph nodes. Traditionally, the standard method islymphography. Lymphography involves injecting radiocontrast agents intopatients and visualize the lymph nodes and lymphatic vessels with X-ray.This procedure is invasive, causes significant discomfort and involvesusing radioactive agents.

In recent years, cross sectional imaging modalities, includingComputational Tomography (CT) and Magnetic Resonance Imaging (MRI), havebecome increasingly popular, in replacement of lymphography in lymphnode visualization. Ultrasound and Positron Emission Tomography (PET)have also been demonstrated to be useful. Although with these techniquesmentioned above, doctors are able to identify lymph nodes and make areasonably accurate judgment of their conditions, they aregeneral-purpose imaging modalities, so their working mechanisms are notdesigned to give the best contrast for lymph nodes specifically, unlessspecific contrasting agents are injected. As a result, other organs andtissues show up in these images with the same or sometimes even bettercontrast compared to lymph nodes, causing distractions to the task offinding and examining the lymph nodes. These general-purposed imagingmodalities are not only not specific to lymph nodes, but also possesstheir own critical drawbacks. CT involves X-ray exposure and PETinvolves radioactive agents, which need to be carefully controlled inprevention of health hazards. MRI requires expensive instrumentation andis not compatible with patients with metal implants. Ultrasound provideslow imaging contrast and resolution mainly because of its long imagingwavelength.

Another common practice for lymph node imaging involves injecting dyes,either blue dyes or fluorescent dyes. The most common dye used for lymphnode visualization is methylene blue, which is actually toxic. Thedosage of this dye has to be carefully managed. Indocyanine green, afluorescent dye, has also been used for lymph node imaging. Systemsleveraging fluorescence dyes such indocyanine green and methylene blueinclude systems a FLARE™ system, a fluobeam system, SPY, FDPM, and aPhotodynamic Eye system. Most of these use either a single image sensor(typically, a CCD) to capture visible (a reference image) andfluorescence images sequentially, or multiple cameras to image differentspectra simultaneously or sequentially.

Dye based methods have numerous drawbacks. One drawback is that dyes canstimulate negative responses to some patients, especially people withkidney complications. Another drawback is that the dye injection methodcan be unreliable because of the leaky nature of the lymphatic system.Additionally, certain dye-based methods require invasive application ofthe dye.

For imaging systems that produce multiple images with the use ofmultiple cameras and/or sequential image acquisition, subsequent imageregistration is required. To properly coordinate differences in spatialparameters of the multiple images, such image processing must take intoaccount changes in angular coordinate, potential relative motion betweenthe system and the subject, or both. Other types of imagers includespecialized CMOS sensors that can collect light via red-green-bluechannel(s) (RGB) as well as a single channel in NIR-1.

There are some other reports in academic papers about using noveloptical techniques to image lymph nodes, including optical speckleimaging, optical coherence tomography, etc. However, optical speckleimaging is highly susceptible to motion artifact, and optical coherencetomography involves sophisticated instrumentation and offers poorimaging contrast.

In summary, given the critical importance of lymph nodes to humanhealth, there are no convenient and highly effective methods forvisualizing lymph nodes. Cross sectional imaging methods are notconvenient and not specific for visualization of lymph nodes unlesscontrasting agents are injected. Dye-based imaging techniques aregenerally highly invasive and incompatible with clinical settings likeroutine checks. A new imaging modality that is able to convenientlyimage lymph nodes with high specificity, high contrast without injectingany imaging contrasting agents will be a powerful tool for medicalpractitioners to examine the health of the patients, evaluate theeffectiveness of a certain treatment, stage one's cancer condition, andso many other medical applications.

SUMMARY

The following is intended to give a brief summary of the disclosure andis not intended to limit the scope of the disclosure.

In one aspect, the present disclosure provides a system for imaging alymphatic component. The system includes an optical source configured toprovide infrared illumination having a polarization to a region of asubject having at least one lymphatic component, a sensor configured tosense a reflected portion of the infrared illumination having anopposite polarization to that of the polarization of illuminationdirectly reflected from the region, and a controller in communicationwith the sensor. The controller is configured to receive, from thesensor, information corresponding to the reflected portion of theinfrared illumination, generate at least one image indicative of the atleast one lymphatic component in the subject using the information, andoutput the at least one image to at least one of a display and/or amemory.

In another aspect, the present disclosure provides a method for imaginglymph nodes or lymphatic vessels in vivo without a contrast agent. Themethod includes providing, using an optical source, an infraredillumination having a polarization to an in vivo region of a subjecthaving lymph nodes or lymphatic vessels that are free of a contrastagent, detecting a reflected portion of the infrared illuminationdirectly reflected from the region and having a opposite polarization tothe polarization using a sensor positioned to receive the illuminationdirectly reflected from the region, and generating at least one imageindicative of the lymph nodes or lymphatic vessels that are free of acontrast agent in the subject using the reflected portion of theinfrared illumination.

In yet another aspect, the present disclosure provides a method forimaging lymph nodes or lymphatic vessels without a mirror. The methodincludes providing, using an optical source, an infrared illumination toa region of a subject having lymph nodes or lymphatic vessels, detectinga reflected portion of the infrared illumination directly reflected fromthe region using a sensor positioned to receive the illuminationdirectly reflected from the region, and generating at least one imageindicative of the lymph nodes or lymphatic vessels in the subject usingthe reflected portion of the infrared illumination.

In a further aspect, a system for imaging a lymphatic component isprovided. The system includes an optical source configured to provideinfrared illumination having a polarization to a region of a subjecthaving at least one lymphatic component, a sensor configured to sense areflected portion of the infrared illumination having an oppositepolarization to that of the polarization directly reflected from theregion, generate at least one image indicative of the at least onelymphatic component in the subject based on the reflected portion of theinfrared illumination, and output the at least one image to at least oneof an external display or an external memory.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic diagram of an example of an imaging system inaccordance with certain aspects of the present disclosure.

FIG. 2 illustrates another example of an imaging system in accordancewith certain aspects of the present disclosure.

FIG. 3 shows a schematic diagram of yet another exemplary embodiment ofan imaging system in accordance with certain aspects of the presentdisclosure.

FIG. 4 shows an example of hardware that can be used to implement acomputing device and an interface platform shown in FIG. 3 in accordancewith some embodiments of the disclosed subject matter.

FIG. 5 shows an exemplary flowchart of a process included in an imagegeneration and analysis application.

FIG. 6 shows an exemplary flowchart of another process included in theimage generation and analysis application.

FIG. 7A shows imaging results of a region imaged without usingpolarizers.

FIG. 7B shows imaging results of the same region as FIG. 7A imaged usingpolarizers.

FIG. 8A shows an image of a region of a mouse taken with a standardcamera.

FIG. 8B shows an image of the region of the mouse of FIG. 8A taken usingan imaging system before an adjuvant is injected.

FIG. 8C shows an image of the region of the mouse of FIG. 8A taken usingthe imaging system forty-eight hours after the adjuvant is injected.

FIG. 9A shows an image of a region of a mouse taken with a standardcamera.

FIG. 9B shows an image of the region of the mouse of FIG. 9A taken usingan imaging system before an adjuvant is injected.

FIG. 9C shows an image of the region of the mouse of FIG. 9A taken usingthe imaging system forty-eight hours after the adjuvant is injected.

FIG. 10A shows an exemplary image taken with an InGaAs camera when anillumination wavelength of 1000 nm was used.

FIG. 10B shows an exemplary image taken with an InGaAs camera when anillumination wavelength of 1175 nm was used.

FIG. 10C shows an exemplary image taken with an InGaAs camera when anillumination wavelength of 1250 nm was used.

FIG. 10D shows an exemplary image taken with an InGaAs camera when anillumination wavelength of 1375 nm was used.

FIG. 10E shows an exemplary image taken with an InGaAs camera when anillumination wavelength of 1550 nm was used.

FIG. 11A shows an image including a lymph node generated using 690 nmwavelength illumination.

FIG. 11B shows an image including the lymph node of FIG. 11A of FIG. 11Agenerated using 730 nm wavelength illumination.

FIG. 11C shows an image including the lymph node of FIG. 11A generatedusing 810 nm wavelength illumination.

FIG. 11D shows an image including the lymph node of FIG. 11A generatedusing 900-950 nm wavelength illumination.

FIG. 11E shows an image including the lymph node of FIG. 11A generatedusing 1000 nm wavelength illumination.

FIG. 11F shows an image including the lymph node of FIG. 11A generatedusing 1125 nm wavelength illumination.

FIG. 11G shows an image including the lymph node of FIG. 11A generatedusing 1175 nm wavelength illumination.

FIG. 11H shows an image including the lymph node of FIG. 11A generatedusing 1250 nm wavelength illumination.

FIG. 111 shows an image including the lymph node of FIG. 11A generatedusing 1300 nm wavelength illumination.

FIG. 11J shows an image including the lymph node of FIG. 11A generatedusing 1375 nm wavelength illumination.

FIG. 11K shows an image including the lymph node of FIG. 11A generatedusing 1550 nm wavelength illumination.

FIG. 11L shows an image including the lymph node of FIG. 11A generatedusing 1575 nm wavelength illumination.

FIG. 11M shows an image including the lymph node of FIG. 11A generatedusing 8-10 μm wavelength illumination.

FIG. 12A shows an image of tissue generated using a regular camera andambient visible light.

FIG. 12B shows an image of the tissue of FIG. 12A generated using anembodiment of the imaging system of FIG. 3 .

DETAILED DESCRIPTION

In one exemplary embodiment, depicted in FIG. 1 , an imaging system 100is provided for imaging lymphatic components. As used herein lymphaticcomponents can include at least one of a lymph node or a lymphaticvessel. The imaging system 100 can include a LED light source 101emitting between 900 and 1300 nm used as the light source. The LED lightsource 101 may also be referred to as the light source 101. The imagingsystem 100 can include a linear polarizer 102 mounted on a rotationalmount and placed in front of the LED light source 101 to create linearlypolarized illumination light 107 (i.e., illumination). The linearpolarizer 102 can include linear polarizing film. The linearly polarizedillumination 107 is shone onto a subject of interest 105, which can beeither a human, as depicted in FIG. 1 , or an animal.

The light source 101 can be oriented towards an in vivo target region106 of the subject of interest 105. The in vivo target region 106 mayalso be referred to as an in vivo region or target region herein. Insome embodiments, the target region 106 may be an ex vivo region such asa tissue portion. The ex vivo tissue portion may include fat, lymphnodes, and/or lymphatic vessels, and the lymph nodes, and/or lymphaticvessels can be imaged as if the tissue portion was in vivo.

Some light sources, such as certain lasers, are inherently linearlypolarized. In the case of these inherently linearly polarized lightsources, creating linearly polarized illumination does not require theuse of linear polarizers. Thus, the linear polarizer 102 may not berequired when the light source 101 is inherently linearly polarized. Inother words, some imaging systems may not include the linear polarizer102. Polarized illumination helps improve the imaging contrast of thistechnique, but is not necessary. A clear contrast of the lymph nodes canbe formed even without any polarizers, as shown in FIGS. 7A-B.

Still referring to FIG. 1 , the imaging system 100 can include a sensor104, which can be a camera. The sensor 104 is used to visualize theilluminated area on a human or an animal. The light source can beoriented towards the target region 106 of the subject of interest 105.The imaging system 100 can include another linear polarizer 103, whichmay be referred to as the sensor linear polarizer 103. The sensor linearpolarizer 104 can include linear polarizing film. The sensor linearpolarizer 103 can be placed in front of the sensor 104 and/or positionedbetween the sensor 104 and the target region 106.

An ideal imaging contrast can be formed when the polarization ofincoming light 108 before the sensor 104 and the polarizer 103 in frontof the sensor 104 is orthogonal to the polarizer 103 in front of thesensor 104. The incoming light can include a portion of the linearlypolarized illumination 107 that has interacted with tissues in the invivo region 106. In principle, linearly polarized illumination remainsmostly linearly polarized when reflecting off the surface of human oranimal skin. The polarization of linearly polarized light does notchange when bouncing directly away from the surface of the skin. Only asmall portion of the light became randomly polarized, because ittraveled relatively deeply into the biological tissues, which serves asrandomly scattering media. By placing the sensor linear polarizer 103 infront of the sensor 104 orthogonal to the direction of the incominglight 108, the sensor linear polarizer 103 filters out the lightreflected by the surface of human or animal skins and lets through onlythe portion of the light 107 emitted from light source 101 thatinteracted with deeper tissues. When the light reflected from thesurface of the skin (i.e., surface glare) is reduced to the minimumlevel, the imaging system 100 achieves the best contrast and deepestpenetration depth. In practice, this ideal contrast can be formed byrotating one of the polarizers, either the sensor linear polarizer 103or the linear polarizer 102 in front of the light source 101, until thelowest overall intensity detected by the sensor 104 is reached. Thelowest overall intensity can be associated with a threshold contrastlevel. The threshold contract level can be within a predetermined rangeof the lowest overall intensity, such as within ten percent of thelowest overall intensity, and the polarizer (e.g., the sensor linearpolarizer 103 or the linear polarizer 102 in front of the light source101) and/or light source 101 can be adjusted until the thresholdcontract level is achieved at the sensor 104.

After linearly polarized photons interact with tissue in the targetregion 106 and go through scattering, the linearly polarized photonsslowly lose their linear polarization. After around, for example, tenscattering events, the linearly polarized photons become completelydepolarized photons. These completely-depolarized photons then reach thesensor linear polarizer 103 in front of the sensor 104. Because thesensor linear polarizer 103 in front of the sensor 104 is approximatelyorthogonal to the linear polarizer 102 in front of the light source 101,only the photons that are now completely depolarized and have theopposite polarization are allowed to be detected by the sensor 104.Therefore, only the photons that interacted at a deeper level with thetissue in the target region 106 are “selected” to be analyzed, andsurface glare and unnecessary surface features are removed.

When the wavelength of light emitted from the light source 101 is muchlonger than visible light (e.g., 1550 nm), imaging quality can beimproved further. Longer wavelengths are associated with lowerscattering effect. As a result, much thicker tissue is required tocompletely depolarize linearly polarized light with longer wavelengthsas compared to linearly polarized light with shorter wavelengths.Imaging systems, such as the imaging system 100, can therefore providelight having longer wavelengths to the subject (e.g., the subject 105)in order better image deeper tissues as compared to shorter wavelengths(e.g., wavelengths in the visible light spectrum).

In the case that the light source 101 is a laser that is alreadylinearly polarized without using a polarizer, the threshold contrastlevel be met by rotating either the sensor linear polarizer 103 or thelaser itself. The relative orthogonal relationship is important and theabsolute directions of polarization are not. The optimal contrast can beachieved through either rotating polarizers, light sources, or sensors,as long as the orthogonal polarization relationship is met. It is notedthat the imaging system 100 of FIG. 1 does not require a mirror, anddoes not require a mirror or other reflective surface as is common incertain imaging techniques, which can reduce the cost to build theimaging system 100 of FIG. 1 as compared to other imaging techniques.

The present disclosure recognizes that lymph nodes are birefringent,i.e. responsive to polarized light. Lymph nodes and/or lymph vessels cancontain collagen, which is birefringent. Furthermore, the tissuessurrounding the lymph nodes such as layers of fat (i.e. lipids) aregenerally not birefringent. Thus, the present disclosure recognizes thatcross-polarization, i.e. the orthogonal polarization relationshipdescribed above, can be used to exploit the difference in birefringencebetween lymph nodes and/or lymph vessels and the surrounding tissue inorder to generate an image of the lymph nodes and/or lymph vessels. Insome embodiments, the light source 101 may provide illumination with awavelength of 1200-1600 nm, which can correspond to one or moreabsorption peaks of the collagen in lymph nodes and/or lymph vesselsincluded in the target region 106. Using illumination wavelengths of1200-1600 nm can therefore improve the imaging contrast between thelymph nodes and/or lymph vessels and the surrounding tissue. Asdescribed above, longer wavelengths may improve the imaging resolutionof the lymph nodes and/or lymph vessels due to reduced scatteringeffects.

Additionally, illumination that includes longer wavelength light,especially 1550 nm wavelength light, can improve the contrast oflymphatic components in the target region 106. Generally, the lymphaticcomponents are surrounded by fat. Lymph nodes and lymphatic vessels arehigh in water, while fat is very low in water. Absorption of photonsoccurs at 1550 nm in water, which is likely why using 1550 nm wavelengthlight to illuminate the target region 106 can improve the contrast (andtherefore visibility) of the lymph nodes and/or lymphatic vessels inimages generated using the imaging system 100. When generating imagesusing 1550 nm illumination wavelength light, lymph nodes and lymphaticvessels appear dark, while fat is bright.

Furthermore, illumination that includes longer wavelength light,especially 1550 nm wavelength light, can improve the contrast oflymphatic components against surrounding blood in the target region 106.While blood contains a high amount of water, blood also contains a highamount of cells. The cells are highly scattering and overwhelm the waterabsorption effect. In testing, the imaging system 100 has been shown togenerate images where blood and/or hemorrhage in the target region 106are not visible, even compared to fat. Suppressing the visibility ofblood and/or hemorrhage is an advantage of the imaging system 100 overother imaging modalities that generate images with visible blood and/orhemorrhages. Hemorrhages can be mistaken as lymph nodes, and are thenharvested to be analyzed. Suppressing and/or removing hemorrhages fromimages may reduce the number of false positives that pathologistsidentify when diagnosing patients.

While the imaging system 100 has been described as being applied to anin vivo region of a subject, it is appreciated the imaging system canalso be applied to an ex vivo tissue specimen as well. For example, thetarget region 106 can include a tissue packet that can include lymphnodes and fat. The tissue packet may have been removed from the subject105 during a lymphadenectomy procedure performed after a tumor andrelevant lymph nodes have been identified. The lymph nodes may then needto be separated from the fat and any other surrounding tissue includedin the tissue packet during a grossing step. Typically, pathologistsremove the lymph nodes via manual palpation and visual inspection, whichis prone to error because lymph nodes are often translucent and appearsimilar to fat, lymph nodes may be as small as 1 mm across, and thelocations of lymph nodes are often unpredictable. The imaging system 100can be used to visualize the lymph nodes and display the lymph nodes tothe pathologist, who can then efficiently and accurately remove thelymph nodes from the target region 106. Cancer organizations may requirea certain number of lymph nodes to be examined for specific types ofcancer. The number of lymph nodes required may range from twelve tothirty-eight. The imaging system 100 can, therefore, help thepathologist acquire the required number of lymph nodes by potentiallyreducing the number of lymph nodes missed in the target region 106.

In FIG. 2 , an illustration of another exemplary embodiment of animaging system 200 is shown. In this exemplary imaging system 200, ahalogen lamp with continuous light illumination is used as a lightsource 201. In order to reduce background from direct reflection atwavelengths out of the range of 900-1300 nm, longpass filters withcut-off wavelengths at 900 nm or 1000 nm are used to filter out lightwith shorter wavelengths. The imaging system 200 can include a primarylongpass filter 203 and a secondary longpass filter 205. Each of theprimary longpass filter 203 and the secondary longpass filter 205 canhave a cut-off wavelength selected from 900 nm to 1000 nm, inclusive.The imaging system 200 can include a linear polarizer 202 on a screwmount. The linear polarizer 202 can include linear polarizing film. Thelinear polarizer 202 can be placed in front of the light source 201 tomake the illumination light from the light source 201 (e.g., the halogenlamp) linearly polarized. The primary longpass filter 203 can be placedin front of light source 201 in order to filter out as much lightemitted from the light source 201 that is below the cut-off wavelengthas possible.

A regular commercially available silicon camera is used as a sensor 204included in the imaging system 200. In some embodiments, a black siliconcamera and/or an InGaAs camera can be used as the sensor 204. A sensorlinear polarizer 206 is placed in front of the sensor 204 on a screwmount. The sensor linear polarizer 206 can include linear polarizingfilm. A lens (not shown), which may be a telecentric lens, is alsoplaced in front of the sensor 204 to form an image. The telecentric lenscan enhance the measurement accuracy of the imaging system 200 byhelping to normalize the size of a lymph node in an image generatedusing the sensor 204 regardless of how far away the lymph node is fromthe sensor 204. The primary longpass filter 203 was also placed in frontof the sensor 204 to filter out the unwanted background from eitherambient light or the light source 201 (e.g., the halogen lamp). In someembodiments, there may not be a need to calibrate the sensor 204 fordifferent ambient and/or background light amounts because the secondarylongpass filter 205 can eliminate background light, which may includevisible frequencies below the cutoff frequency of the secondary longpassfilter 205. Eliminating the need to calibrate the sensor 204 can savetime in detecting the lymphatic components, as well as make the imagingsystem 200 more robust as compared to an imaging system that requirescalibration of one or more sensors. The light source 201 and the sensor204 should both point at the same area of interest on the subject beingstudied, either a human or an animal, such as a person 207 as shown inFIG. 2 . It is noted that the imaging system 200 of FIG. 2 does notinclude a mirror, and does not require a mirror or other reflectivesurface as is common in certain imaging techniques. This can reduce thecost to build the imaging system 200 of FIG. 2 as compared to otherimaging systems and/or techniques.

In some embodiments, a controller (not shown) may be included in theimaging system 200. The controller can be coupled to an optical sourcesuch as a laser or LED, as well as a sensor such as a camera. Thecontroller can be coupled to and in communication with the opticalsource and the sensor. The controller can be configured to cause theoptical source to provide the infrared illumination to the region bycontrolling power supplied to the optical source. The controller canalso receive information from the sensor corresponding to the infraredillumination reflected from the subject. The infrared illuminationreflected can be referred to as a reflected portion of the infraredillumination that was originally supplied by the optical source. Thecontroller can also generate at least one image indicative of the lymphnodes in the subject using the information received.

Referring now to FIGS. 1 and 2 as well as FIG. 3 , a schematic diagramof yet another exemplary embodiment of an imaging system 300 is shown.In some embodiments, the imaging system 300 can be approximately thesize of a shoebox, and can therefore be a bench-top imaging device. Theimaging system 300 can include an interface platform 302. The interfaceplatform 302 can include at least one memory, at least one processor,and any number of connection interfaces capable of communication withsensors and optical sources (not shown). The interface platform 302 canalso store (e.g., in the at least one memory) and execute (e.g., usingthe at least one processor) at least a portion of an image generationand analysis application 304. As will be described below, the interfaceplatform 302 can be coupled to and in communication with a computingdevice 334 included in the imaging system 300 that may also store and/orexecute at least a portion of the image generation and analysisapplication 304. The interface platform 302 can be a controller, alaptop computer, a desktop computer, or another device capable ofreceiving signals from a sensor and outputting control signals to anoptical source. The controller can be a microcontroller, such as aRaspberry Pi 4 Model B. In some embodiments, the controller can be anIntel® NUC computer configured to operate using a Windows operatingsystem.

The interface platform 302 can be coupled to and in communication withan illumination generation system 306 included in the imaging system300. The illumination generation system 306 can include an opticalsource 308. The interface platform 302 can be coupled to and incommunication with the optical source 308. The interface platform 302can output control signals to the optical source 308 in order to causethe optical source 308 to provide illumination. In some embodiments, theoptical source 308 may output suitable data (e.g., total lifetime hoursof operation) to the interface platform 302. The illumination generationsystem 306, and more specifically, the optical source 308, can beoriented to provide illumination 314 to a target region 318 that may bein vivo (e.g., included in a subject 316 such as a patient) or ex vivo,as will be described further below. The illumination 314 output by theillumination generation system 306 can be referred to as the providedillumination 314. The illumination 314 can be infrared illumination. Theinfrared illumination can include light in the near-infrared range(800-1400 nm wavelength) and/or light in the short-wave infrared range(1400-3000 nm wavelength).

The optical source 308 can include at least one of an LED such as asingle LED, a plurality of LEDs such as an LED array, a halogen lampsuch as a tungsten halogen lamp, a quartz-halogen lamp, or a quartziodine lamp, a laser, or another suitable optical source capable ofoutputting light at one or more predetermined wavelengths. In someembodiments, the optical source 308 may output one or more discretewavelengths of light, such as 1550 nm, 1375 nm, 1300 nm, and/or otherwavelengths selected from 800 nm to 1700 nm wavelengths. For example,the optical source 308 may only output 1550 nm wavelength light. In someembodiments, the optical source can output one or more discretefrequencies from a subrange of wavelengths within the 800 nm to 2000 nmrange, such as a subrange of 1200-1600 nm wavelengths. In someembodiments, the optical source 308 may output a continuous range ofwavelengths of light, such as 900-1300 nm, 1500-1600 nm, 1200-1600 nm,1000-1700nm (i.e., near-infrared), and/or other ranges of wavelengthswithin 800-2000 nm. In some embodiments, the optical source 308 may bethe light source 101 of FIG. 1 or the light source 201 of FIG. 2 . Inparticular, the optical source 308 may output longer wavelength light,especially 1550 nm wavelength light, in order to better contrastlymphatic components against surrounding fat, blood, and/or hemorrhagesas described above. For the imaging system 300 to function properly, theoptical source 308 does not need to emit a range of wavelengths oflight. In testing, excellent imaging has been obtained using only 1550nm wavelength light. However, the imaging system 300 can performsuitable imaging using multiple wavelengths of light. It is contemplatedthat light with wavelengths up to 2600 nm could be used, as some sensorssuch as certain InGaAs cameras stop responding beyond 2600 nm. Thus,light with wavelengths ranging from 800-2600 nm might be used in theimaging system 300. In testing, light with wavelengths below 800 nm hasnot performed as well as light with higher wavelengths, such as 800-1700nm.

In some embodiments, the illumination generation system 306 can includea polarizer 310 such as a linear polarizer. For certain optical sourcesthat are not inherently polarized, such as halogen optical sources, theimaging system 300 may include a polarizer 310. The polarizer 310 caninclude linear polarizing film. The polarizer 310 can be mounted andplaced in front of the optical source 310 to create linearly polarizedillumination light. The polarizer 310 can be mounted on a rotationalmount or other suitable mount to allow for adjustment of the polarizer310. Thus, the illumination 314 provided to the target region 318 can belinearly polarized. Polarized illumination can improve imaging contrastin images generated by the imaging system 300, but it is not necessary.In some embodiments, the polarizer 310 may be the linear polarizer 102of FIG. 1 or the linear polarizer 202 of FIG. 2 . If the optical source308 is an inherently polarized device, such as certain lasers, thepolarizer 310 may not be included in the imaging system 300. In someembodiments, the polarizer 310 can be a circular polarizer.

In some embodiments, the illumination generation system 306 can includean optical filter 312. The optical filter 312 can be a longpass filtersuch as a cold mirror, a colored glass filter, a thermoset allyldiglycol carbonate (ADC) filter, or another suitable filter capable ofattenuating lower wavelength light (e.g., visible light) and passinghigher wavelength light (e.g., infrared light). The longpass filter mayhave a cut-off wavelength of no less than 800 nm. For example, thecut-off wavelength may be 800 nm, 900 nm, or 1000 nm. The optical filter312 can be placed in front of light source optical source 308 in orderto filter out as much light emitted from the optical source 308 that isbelow the cut-off wavelength as possible. In some embodiments, theoptical filter 312 may be the primary longpass filter 203 of FIG. 2 . Insome embodiments, the optical filter 312 can be a bandpass filter suchas a hard coated filter or a colored glass filter. The bandpass filtermay only pass a range of light wavelengths within a 800-2000 nm window,or a subrange of the 800-2000 nm window. For example, the bandpassfilter may only pass 900-1700 nm wavelength light. Thus, theillumination 314 provided to the target region 318 can be longpassfiltered or bandpass filtered.

The optical source 308, the polarizer 310, and/or the optical filter 312can be physically arranged (i.e., positioned) relative to each other asshown in FIG. 1 and/or FIG. 2 . For example, the optical source 308 andthe polarizer 310 can be arranged in similar fashion to the light source101 and the linear polarizer 102, respectively, as shown in FIG. 1 . Asanother example, the optical source 308, the polarizer 310, and theoptical filter 312 can be arranged in similar fashion to the lightsource 201, the linear polarizer 202, and the longpass filter 203,respectively, as shown in FIG. 2 . The optical source 308 can output theillumination 314 that may pass through and be polarized by the polarizer310 and/or pass through and be attenuated by the optical filter 312. Theillumination 314, which may be polarized and/or attenuated, is thenprovided to the target region 318.

As mentioned above, the optical source 308, and by extension theillumination generation system 306, can be oriented to provide theillumination 314 to the target region 318. In some embodiments, thetarget region 318 can be an in vivo region included in the subject 316.In these embodiments, the target region 318 may be referred to as the invivo region. The subject 316 can be a human patient. In otherembodiments, the target region 318 can be an ex vivo region. In theseembodiments, the target region 318 may be referred to as the ex vivoregion. For example, the target region 318 can be a tissue portionremoved from a subject for grossing purposes as described above. Theimaging system 300 can be used to aid in the grossing of the tissueportion by visualizing lymphatic components for a practitioner.

At least a portion of the illumination 314 can be provided to the targetregion 318. The target region 318 may include one or more lymphaticcomponents. The provided illumination 314 can interact with thelymphatic components and the surrounding tissue in the target region318. At least a portion of the provided illumination 314 may becomerandomly polarized as described above. At least a portion of theprovided illumination 314 can be reflected as reflected illumination320. The reflected illumination 320 can include light that hasinteracted with deep tissue in the target region 318.

The interface platform 302 can be coupled to and in communication with asensing system 322 included in the imaging system 300. The sensingsystem 322 can include a sensor 324. The interface platform 302 can becoupled to and in communication with the sensor 324. The sensor 324 cansense the reflected illumination 320 and output signals associated withan image based on the sensed reflected illumination 320. The interfaceplatform 302 can receive the signals indicative of the image from thesensor 324. The signals can include information about the image. In someembodiments, the information can include the image formatted in apredetermined image format such as PNG, JPEG, DICOM (i.e., included in aDICOM file), etc. In some embodiments, the information can also includemetadata about the image, such as the time the image was taken or apatient associated with the image. In some embodiments, the sensor 324can include a camera, such as a silicon camera including a siliconcomplementary metal oxide semiconductor (CMOS) camera or a siliconcharge-coupled device (CCD) camera with phosphor coating, a germaniumcamera, a germanium-tin on silicon camera, a black silicon camera, aquantum dot shortwave infrared (SWIR) camera, and/or an InGaAs camera.The InGaAs camera may be a nitrogen cooled InGaAs camera. The sensor 324can include a mercury-cadmium-telluride (HgCdTe or MCT) camera. Thesensor 324 can be responsive to light including at least a portion ofthe light ranging from 800 nm-2000 nm in wavelength, especiallywavelengths at or near 1550 nm. It is noted that the imaging system 300may only require a single sensor (e.g., a silicon camera), in contrastto other systems that may require multiple sensors and/or cameras.

The sensing system 322 can include a lens 326 positioned in front of thesensor 324. In some embodiments, the lens 326 can be integral with thesensor 324, such as if the sensor 324 and the lens 326 are sold as asingle off-the-shelf component. The lens 326 can improve the imagingcapabilities of the sensor 324. For example, the lens 326 can be atelecentric lens. The telecentric lens can enhance the measurementaccuracy of the imaging system 300 by helping to normalize the size of alymph node in an image generated using the sensor 324 regardless of howfar away the lymph node is from the sensor 324.

In some embodiments, the sensing system 300 can include a light diffuser328 such as a piece of frosted glass or a tissue paper. The lightdiffuser 328 can be inserted between the lens 326 and a polarizer 332that can be included in the sensing system 322. The light diffuser 328can create a more evenly distributed light pattern in the reflectedillumination 320. The light diffuser 328 may improve the imagingcapabilities of the sensor 324 as a result of the more evenlydistributed light pattern.

In some embodiments, the sensing system 322 can include an opticalfilter 330 positioned in front of the sensor 324. The optical filter 330can be a longpass filter such as a cold mirror, a colored glass filter,a thermoset ADC filter, or another suitable filter capable ofattenuating lower wavelength light (e.g., visible light) and passinghigher wavelength light (e.g., infrared light). The longpass filter canhave a cut-off wavelength of no less than 800 nm. For example, thecut-off wavelength may be 800 nm, 900 nm, or 1000 nm. In someembodiments, there may not be a need to calibrate the sensor 324 fordifferent ambient and/or background light amounts because the opticalfilter 330 can eliminate background light, which may include visiblefrequencies below the cutoff frequency of the optical filter 330. Insome embodiments, the optical filter 330 may be the secondary longpassfilter 205 as shown in FIG. 2 . In some embodiments, the optical filter330 can be a bandpass filter such as a hard coated filter or a coloredglass filter. The bandpass filter may only pass a range of lightwavelengths within a 800-2000 nm window, or a subrange of the 800-2000nm window. For example, the bandpass filter may only pass 900-1700 nmwavelength light. Thus, the reflected illumination 320 provided to thesensor 324 can be longpass filtered or bandpass filtered.

As mentioned above, the sensing system can include the polarizer 332.The polarizer 332 can be a linear polarizer. In some embodiments, thepolarizer 332 can be a circular polarizer. The polarizer 332 can beplaced in front of the sensor 324. The polarizer 332 can include linearpolarizing film. Similar to the polarizer 310 included in theillumination generation system 306, the polarizer 332 included in thesensing system 322 can be mounted on a rotational mount or othersuitable mount to allow for adjustment. The linear polarizers 310, 332,can be rotated or otherwise adjusted to create an ideal imaging contrastas described above. The polarizer 332 can remove any light having thesame polarization as the provided illumination 314 from the reflectedillumination 320. The sensor 324 can detect light included in thereflected illumination 320 having the opposite polarization as theprovided illumination 314.

In some embodiments, the sensor 324 can be coupled to and incommunication with the external display 372. Alternatively or inaddition, the sensor 324 can be coupled to and in communication with amemory 374 that may be included in the imaging system 300 or external tothe imaging system 300. For example, the memory 374 can be flash memoryincluded in a memory card. In embodiments where the sensor 324 iscoupled to and in communication with the external display 372 and/or thememory 374, the sensor 324 can be configured to sense the reflectedportion of the provided illumination 314 and generate at least one imageindicative of the any lymphatic components in the target region 318based on the reflected portion (i.e., the reflected illumination 320) ofthe provided illumination 314. The sensor 324 may also be configured tooutput the at least one image to at least one of the external display372 or the memory 374.

In some embodiments, the optical source 308 may not be coupled to acontroller or other device, and may only need to be coupled to a powersource. In these embodiments, the optical source 308 can provide theillumination 314 to the target region 318 constantly or semi-constantly.In some embodiments, the interface platform 304 can supply power to theoptical source 308 (i.e., act as the power source). In otherembodiments, the optical source 308 can receive power from wall power,one or more batteries, or another suitable power source.

In some embodiments, the sensor 324 can be coupled to the externaldisplay 372 and/or the memory 374, and the optical source may be coupledto a power supply without being coupled to the interface platform 304and/or other suitable device. Thus, the imaging system 300 can beimplemented without the use of a controller or computational device.

In some embodiments, the imaging system 300 can be Class-1,510(k)-exempt, and/or good manufacturing practice (GMP) exempt.

The imaging system 300 may also include the external display 372 and/orthe computing device 334. As mentioned above, the interface platform 302can be coupled to and in communication with the computing device 334.The imaging system 300 can include a communication network 336. Thecommunication network 336 can facilitate communication between theinterface platform 302 and the computing device 334. The interfaceplatform 302 can also be coupled to and in communication with theexternal display 372.

In some embodiments, communication network 336 can be any suitablecommunication network or combination of communication networks. Forexample, communication network 336 can include a Wi-Fi network (whichcan include one or more wireless routers, one or more switches, etc.), apeer-to-peer network (e.g., a Bluetooth network), a cellular network(e.g., a 3G network, a 4G network, etc., complying with any suitablestandard, such as CDMA, GSM, LTE, LTE Advanced, WiMAX, etc.), a wirednetwork, etc. In some embodiments, communication network 336 can be alocal area network, a wide area network, a public network (e.g., theInternet), a private or semi-private network (e.g., a corporate oruniversity intranet), any other suitable type of network, or anysuitable combination of networks. Communications links shown in FIG. 3can each be any suitable communications link or combination ofcommunications links, such as wired links, fiber optic links, Wi-Filinks, Bluetooth links, cellular links, etc. In some embodiments, thecomputing device 334 can implement portions of the image generation andanalysis application 304.

Referring now to FIG. 3 as well as FIG. 4 , an example of hardware thatcan be used to implement a computing device 334 and an interfaceplatform 302 shown in FIG. 3 in accordance with some embodiments of thedisclosed subject matter is shown. As shown in FIG. 4 , the computingdevice 334 can include a processor 350, a display 352, an input 354, acommunication system 356, and memory 358. The processor 350 canimplement at least a portion of the image generation and analysisapplication 304, which can, for example be executed from a program(e.g., saved and retrieved from memory 358). The processor 350 can beany suitable hardware processor or combination of processors, such as acentral processing unit (“CPU”), a graphics processing unit (“GPU”),etc., which can execute a program, which can include the processesdescribed below.

In some embodiments, the display 352 can present a graphical userinterface. In some embodiments, the display 352 can be implemented usingany suitable display devices, such as a computer monitor, a touchscreen,a television, etc. In some embodiments, the inputs 354 of the computingdevice 334 can include indicators, sensors, actuatable buttons, akeyboard, a mouse, a graphical user interface, a touch-screen display,etc. In some embodiments, the inputs 354 can allow a user (e.g., amedical practitioner, such as a radiologist) to interact with thecomputing device 334, and thereby to interact with the interfaceplatform 302 (e.g., via the communication network 336).

In some embodiments, the communication system 356 can include anysuitable hardware, firmware, and/or software for communicating with theother systems, over any suitable communication networks. For example,the communication system 356 can include one or more transceivers, oneor more communication chips and/or chip sets, etc. In a more particularexample, communication system 356 can include hardware, firmware, and/orsoftware that can be used to establish a coaxial connection, a fiberoptic connection, an Ethernet connection, a USB connection, a Wi-Ficonnection, a Bluetooth connection, a cellular connection, etc. In someembodiments, the communication system 356 allows the computing device334 to communicate with the interface platform 302 (e.g., directly, orindirectly such as via the communication network 336).

In some embodiments, the memory 358 can include any suitable storagedevice or devices that can be used to store instructions, values, etc.,that can be used, for example, by processor 350 to present content usingdisplay 352, to communicate with the interface platform 302 viacommunications system(s) 356, etc. Memory 358 can include any suitablevolatile memory, non-volatile memory, storage, or any suitablecombination thereof. For example, memory 358 can include RAM, ROM,EEPROM, one or more flash drives, one or more hard disks, one or moresolid state drives, one or more optical drives, etc. In someembodiments, memory 358 can have encoded thereon a computer program forcontrolling operation of computing device 334 (or interface platform302). In such embodiments, processor 350 can execute at least a portionof the computer program to present content (e.g., user interfaces,images, graphics, tables, reports, etc.), receive content from theinterface platform 302, transmit information to the interface platform302, etc.

As shown in FIG. 4 , the interface platform 302 can include a processor360, a display 362, an input 364, a communication system 366, memory368, and connectors 370. In some embodiments, the processor 360 canimplement at least a portion of the image generation and analysisapplication 304, which can, for example be executed from a program(e.g., saved and retrieved from memory 368). The processor 360 can beany suitable hardware processor or combination of processors, such as acentral processing unit (“CPU”), a graphics processing unit (“GPU”),etc., which can execute a program, which can include the processesdescribed below.

In some embodiments, the display 362 can present a graphical userinterface. In some embodiments, the display 362 can include any suitabledisplay devices, such as a computer monitor, a touchscreen, atelevision, etc. In some embodiments, the inputs 364 of the interfaceplatform 302 can include indicators, sensors, actuatable buttons, akeyboard, a mouse, a graphical user interface, a touch-screen display,and the like. In some embodiments, the inputs 364 allow a user (e.g., afirst responder) to interact with the interface platform 302, andthereby to interact with the computing device 334 (e.g., via thecommunication network 336). The computing device 334 can also be coupledto and in communication with an external display 372 that can provide atleast some of the functionality of the display 352.

As shown in FIG. 4 , the interface platform 302 can include thecommunication system 366. The communication system 366 can include anysuitable hardware, firmware, and/or software for communicating with theother systems, over any suitable communication networks. For example,the communication system 366 can include one or more transceivers, oneor more communication chips and/or chip sets, etc. In a more particularexample, communication system 366 can include hardware, firmware, and/orsoftware that can be used to establish a coaxial connection, a fiberoptic connection, an Ethernet connection, a USB connection, a Wi-Ficonnection, a Bluetooth connection, a cellular connection, etc. In someembodiments, the communication system 366 allows the interface platform302 to communicate with the computing device 334 (e.g., directly, orindirectly such as via the communication network 336). It iscontemplated that the communication system 366 could communicate withthe optical source and/or the sensor 324, and thus provide at least someof the functionality of the connectors 370, which will be describedbelow.

In some embodiments, the memory 368 can include any suitable storagedevice or devices that can be used to store instructions, values, etc.,that can be used, for example, by processor 360 to present content usingdisplay 362, to communicate with the computing device 334 viacommunications system(s) 366, etc. Memory 368 can include any suitablevolatile memory, non-volatile memory, storage, or any suitablecombination thereof. For example, memory 368 can include RAM, ROM,EEPROM, one or more flash drives, one or more hard disks, one or moresolid state drives, one or more optical drives, etc. In someembodiments, memory 368 can have encoded thereon a computer program forcontrolling operation of the interface platform 302 (or computing device334). In such embodiments, processor 360 can execute at least a portionof the computer program to present content (e.g., user interfaces,graphics, tables, reports, etc.), receive content from the computingdevice 334, transmit information to the computing device 334, etc.

In some embodiments, the connectors 370 can be wired connections, suchthat the optical source 308 and the sensor 324 can communicate with theinterface platform 302, and thus can communicate with the computingdevice 334 (e.g., via the communication system 366 and being directly,or indirectly, such as via the communication network 336). Additionallyor alternatively, the optical source 308 and/or the sensor 324 can sendinformation to and/or receive information from the interface platform302 (e.g., using the connectors 370, and/or the communication systems366).

Referring now to FIGS. 3-4 as well as FIG. 5 , an exemplary flowchart ofa process 400 included in the image generation and analysis application304 is shown. In some embodiments, the interface platform 302 and thecomputing device 334 may each execute a portion of the process 400 inorder to generate images of the target region 318, which may containlymphatic components, such as lymph nodes and/or lymphatic vessels. Asdescribed above, the target region 318 can be in vivo (e.g., included inthe subject 316) or ex vivo (e.g., a tissue packet removed from asubject). In some embodiments, the interface platform 302 may executethe entire process 400.

At 402, the process 400 can cause the optical source 308 to provide theillumination 314 to the target region 318. The target region 318 mayinclude lymphatic components. The provided illumination 314 may passthrough the polarizer 310 and/or the optical filter 312. The providedillumination 314 is then provided to the target region 318. At least aportion of the provided illumination 314 can then be reflected as thereflected illumination 320 towards the sensing system 322, as describedabove. The reflected illumination 320 may pass through the polarizer332, the optical filter 330, the light diffuser 328, and/or the lens 326before reaching the sensor 324. In some embodiments, the process 400 maynot need to cause the optical source 308 to provide illumination if theoptical source 308 is continuously or semi-continuously providing theillumination 314 to the target region 318. In other words, in someembodiments, the process 400 may not implement step 402.

At 404, the process 400 can detect a reflected portion of theillumination 314. The reflected portion can be the reflectedillumination 320. The reflected portion can be directly reflected fromthe target region 318. Because the reflected portion is directlyreflected from the target region 318, the system 300 does not requirethe use of a mirror or other reflector to redirect the reflected portiontowards the sensor 324. The process 404 can detect the reflected portionusing the sensor 324. Detecting the reflected portion of theillumination 314 can include receiving signals from the sensor 324 inresponse to the reflected portion.

At 406, the process 400 can generate at least one image indicative ofone or more lymphatic components, such as lymph nodes and lymphaticvessels, if present in the target region 318 using the reflected portionof the illumination 314. The process 400 may generate the at least oneimage based on the signals received from the sensor 324 at 404. Theprocess 400 may generate the image based on the signals from the sensor324. In some embodiments, the signals output by the sensor 324 caninclude the at least one image indicative of the lymphatic components.The process 400 may reformat and/or compress the at least one imagereceived from the sensor. Alternatively, the process 400 may store theat least one image (i.e., in the memory 358 and/or the memory 368) asreceived from the sensor 324.

At 408, the process 400 can output the at least one image to at leastone of a display and/or a memory. The display can be the display 362that can be included in the interface platform 302, the display 352 thatcan be included in the computational device 334, or the external display372. The memory can be the memory 368 included in the interface platform302 or the memory 358 included in the computing device 334. The memorycan be a memory outside the imaging system 300, such as a memoryincluded in a remote server.

Referring now to FIGS. 3-4 as well as FIG. 6 , an exemplary flowchart ofa process 450 included in the image generation and analysis application304 is shown. In some embodiments, the interface platform 302 and thecomputing device 334 may each execute a portion of the process 450 in totrain a segmentation machine learning model and/or a classificationmachine learning model, as well as analyze images produced by an imagingsystem (e.g., the imaging system 300 in FIG. 3 and FIG. 4 ) using thesegmentation machine learning model and/or the classification machinelearning model after the model(s) have been trained.

At 452, the process 450 can receive training data for a segmentationmodel. The segmentation model can be a machine learning model such as aconvolutional neural network. The convolutional neural network mayinclude U-Net network architecture. The training data for thesegmentation model can include raw images and associated segments. Theraw images can be generated using an imaging system such as the imagingsystem 100 in FIG. 1 , the imaging system 200 in FIG. 1 , or the imagingsystem 300 in FIG. 3 . The segments can be areas of the images thateither correspond to lymph nodes or the absence of lymph nodes. In someembodiments, the segments can also include areas that correspond tolymphatic vessels. Thus, the segmentation model can be trained tosegment lymph nodes and lymphatic vessels in images. The segments can bepreviously identified by a qualified practitioner such as an oncologist.In some embodiments, the segmentation model can be a predeterminedalgorithm configured to identify lymph nodes that may not requiretraining.

At 454, the process 450 can receive training data for a classificationmodel. The classification model can be a machine learning model such asa recurrent neural network. The classification model can be trained toclassify entire images. The training data for the classification modelcan include a number of raw images generated using an imaging systemsuch as the imaging system 100 in FIG. 1 , the imaging system 200 inFIG. 1 , or the imaging system 300 in FIG. 3 . The training data canalso include a number of segmented images corresponding to the number ofraw images. The segmented images can be produced by providing the rawimages to the trained segmentation model. In some embodiments, thetraining data can include a classification of each segmented lymph nodeand/or lymphatic vessels. The classification can be malignant orhealthy, and can be provided by a suitable medical practitioner. In someembodiments, each classification can be associated with an entire rawimage included in the training data.

At 456, the process 450 can train the segmentation model using thetraining data for the segmentation model. After the segmentation modelis trained at 456, the segmentation model can be referred to as thetrained segmentation model.

At 458, the process 450 can train the classification model using thetraining data for the classification model. Depending on the trainingdata, the classification model can be trained to identify individuallymphatic components (i.e., lymph nodes and/or lymphatic vessels) asmalignant or healthy, or trained to identify entire images as healthy ormalignant. After the classification model is trained at 456, theclassification model can be referred to as the trained classificationmodel.

At 460, the process 450 can provide an image to the trained segmentationmodel. In some embodiments, the process 450 can sequentially provide anynumber of images to the trained segmentation model at 460.

At 462, the process 450 can receive a number of segments associated withthe image provided to the trained segmentation model. In someembodiments, the process 450 can receive a number of segments for eachimage provided to the trained segmentation model at 460.

At 464, the process 450 can provide an image to the trainedclassification model. In some embodiments, the process 450 cansequentially provide any number of images to the trained classificationmodel at 464.

At 466, the process 450 can receive a classification for the imageprovided to the trained classification model. In some embodiments, theprocess 450 can receive a number of classification associated with thenumber of images provided to the trained model at 464.

At 468, the process 450 can output any received segment(s) and/orclassification(s) to at least one of a display and/or memory. Thedisplay can be the display 362 that can be included in the interfaceplatform 302, the display 352 that can be included in the computationaldevice 334, or the external display 372. The memory can be the memory368 included in the interface platform 302 or the memory 358 included inthe computing device 334. The memory can be a memory outside the imagingsystem 300, such as a memory included in a remote server. Externalprocesses may perform further analysis on the received segments. Forexample, the segments can be used to determine features of eachsegmented lymphatic component, including lymph node size, lymph nodeaspect ratio, lymph node symmetry, lymph node border clarity, lymph nodecurvature, and/or lymphatic vessel patterns. Further analysis can beperformed on the features of each lymphatic component. In someembodiments, the process 450 can output a heat map for each imageidentifying distinguishing features in each raw image (and, byextension, the lymphatic components) that led to the classifications foreach lymphatic component and/or raw image.

It is understood that the image generation and analysis application 304may include one or both of the process 400 of FIG. 5 and the process 450of FIG. 6 . In some embodiments, multiple applications may beimplemented in order to execute one or both of the process 400 of FIG. 5and the process 450 of FIG. 6 .

FIGS. 7A and 7B show imaging results of an imaging system constructed inaccordance with the imaging systems described herein. FIG. 7A showsimaging results of a region imaged without using polarizers. FIG. 7Bshows imaging results of the same region imaged using polarizers. Theregion shown in FIGS. 7A and 7B includes a lymph node 500 The polarizersimprove imaging contrast, but lymph nodes can be visualized with orwithout polarizers.

FIGS. 8A-C shows exemplary imaging results of mice. The imaging systemused includes an LED emitting around 1200 nm light as a light source anda liquid nitrogen cooled InGaAs camera as a sensor. FIG. 8A shows animage of a region of a mouse taken with a standard camera. FIG. 8B showsan image of the region of the mouse taken using the imaging systembefore an adjuvant is injected. A lymph node 504 and a bladder 508 canbe visualized. FIG. 8C shows an image of the region of the mouse takenusing the imaging system forty-eight hours after the adjuvant isinjected. The lymph node 504 and the bladder 508 can be visualized. Theresults show the lymph node 504 has significantly grown in size in theforty-eight hour period after the adjuvant is injected.

FIGS. 9A-C shows exemplary imaging results of mice. The imaging systemused includes a halogen lamp as a light source with longpass filters tofilter light from the lamp, and a standard silicon camera as a sensor,similar to the imaging system 200 in FIG. 2 . FIG. 9A shows an image ofa region of a mouse taken with a standard camera. FIG. 9B shows an imageof the region of the mouse taken using the imaging system before anadjuvant is injected. FIG. 9C shows an image of the region of the mousetaken using the imaging system forty-eight hours after the adjuvant isinjected. The results show the lymph nodes, such as lymph node 512, havesignificantly grown in size in the forty-eight hour period after theadjuvant is injected. The results are similar in quality to moreexpensive systems such as the imaging system 100 shown in FIG. 1 .Furthermore, the imaging system used to generate FIGS. 9B-C is morecompatible with ambient light than other imaging systems.

FIGS. 10A-10E show imaging results of a lymph node using variousillumination wavelengths and an InGaAs camera. FIG. 10A was taken whenan illumination wavelength of 1000 nm was used. FIG. 10B was taken whenan illumination wavelength of 1175 nm was used. FIG. 10C was taken whenan illumination wavelength of 1250 nm was used. FIG. 10D was taken whenan illumination wavelength of 1375 nm was used. FIG. 10E was taken whenan illumination wavelength of 1550 nm was used.

FIGS. 11A-M show imaging results of a lymph node in an ex-vivo pigmesenteric tissue sample. The lymph node was imaged using differentillumination wavelengths and sensors included in an imaging system inaccordance with embodiments of the invention. A single wavelength LEDoptical source was used to generate illumination wavelengths of 690 nmand 730 nm. A continuous wavelength lamp with a bandpass filter was usedgenerate illumination wavelengths ranging from 810 nm to 1575 nm. Acontinuous wavelength lamp without a bandpass filter was used togenerate the 8-10 μm illumination. The 8-10 μm illumination was achievedbecause the sensor used was a heat camera only sensitive to 8-10 μmwavelength light. For 690 nm and 730 nm wavelength illumination, asilicon camera was used as the sensor. For illumination wavelengthsranging from 810 nm to 1575 nm, an InGaAs camera was used as the sensor.For all illumination wavelengths, the imaging system includedorthogonally positioned polarizers. Each individual illuminationwavelength represents the most dominant wavelength in a band ofwavelength.

For each illumination wavelength, the signal-to-noise ratio was measuredin order to measure the performance of the illumination wavelength. Ahigher signal-to-noise ratio is preferable because the lymph node willstand out more against surrounding tissue.

FIG. 11A shows an image including the lymph node generated using 690 nmwavelength illumination. FIG. 11B shows an image including the lymphnode generated using 730 nm wavelength illumination. FIG. 11C shows animage including the lymph node generated using 810 nm wavelengthillumination. FIG. 11D shows an image including the lymph node generatedusing 900-950 nm wavelength illumination. FIG. 11E shows an imageincluding the lymph node generated using 1000 nm wavelengthillumination. FIG. 11F shows an image including the lymph node generatedusing 1125 nm wavelength illumination. FIG. 11G shows an image includingthe lymph node generated using 1175 nm wavelength illumination. FIG. 11Hshows an image including the lymph node generated using 1250 nmwavelength illumination. FIG. 11I shows an image including the lymphnode generated using 1300 nm wavelength illumination. FIG. 11J shows animage including the lymph node generated using 1375 nm wavelengthillumination. FIG. 11K shows an image including the lymph node generatedusing 1550 nm wavelength illumination. FIG. 11L shows an image includingthe lymph node generated using 1575 nm wavelength illumination. FIG. 11Mshows an image including the lymph node generated using 8-10 μmwavelength illumination.

Table 1 below summarizes the signal-to-noise ratio for each illuminationwavelength. The results in Table 1 show that 1550 illuminationwavelength performed the best, with the highest signal-to-noise ratio of24. Illumination wavelengths ranging from 1175-1375 had comparableperformance that provide usable performance. Illumination wavelengths ator below 810 nm had much worse performance than illumination wavelengthsranging from 900-1575 nm. The 8-10 μm wavelength illumination performedsignificantly worse than the 1550 nm or 1575 nm wavelength illumination,suggesting that illumination wavelengths significantly above 1575 nm mayresult in decreased performance.

TABLE 1 Illumination Signal-To- Corresponding Wavelength Noise RatioFIG. 690 nm 4 11A 730 nm 2 11B 810 nm 3 11C 900-950 nm 5 11D 1000 nm 911E 1125 nm 8 11F 1175 nm 10 11G 1250 nm 12 11H 1300 nm 11 11I 1375 nm13 11J 1550 nm 20 11K 1575 nm 24 11L 8-10 μm 8 11M

Referring now to FIG. 12A and FIG. 12B, a comparison of images of alymph node 516 in an ex-vivo human tissue sample generated usingdifferent imaging techniques is shown. FIG. 12A shows an image of thelymph node 516 generated using a regular camera and ambient visiblelight. FIG. 12B shows an image of the lymph node 516 generated using anembodiment of the imaging system 300 of FIG. 3 . The lymph node 516 ismuch more clearly visualized in FIG. 12B.

This disclosure provides various embodiments of imaging systems thateach provide a set of advantages over other imaging systems. Oneadvantage is that the imaging systems are entirely non-invasive andlabel-free. This advantage makes the provided imaging systems stand outagainst the commonly used techniques based on methylene blue,Indocyanine green, and other injected dyes. The imaging systems do notrequire injection or operation (e.g., a cutting operation) to achievehigh imaging contrast of the lymph nodes. It is also noted that thelymph nodes are in vivo when imaged by the imaging system, in contrastto other imaging systems that require lymph nodes and/or surroundingtissue to be removed from a subject in order to perform imaging of thelymph nodes.

Another advantage of the imaging systems provided herein is theincreased safety compared to other imaging modalities. The systems onlyuse infrared light at very low intensity. Images shown in the figureslisted in this document were taken with only 1 mW optical powerillumination, which is thousands of times lower than the exposure limitimposed by regulations. This advantage makes the disclosed imagingsystems stand out against CT, PET, and others that inherently posehealth hazards to patients. This disclosure describes an optical methodfor visualizing lymph nodes conveniently without any injection. Themethod uses illumination light between 800-1700 nm and sensors that areable to detect this wavelength range or part of this wavelength range.The imaging systems can utilize the illumination light to detect lymphnodes using the inherent absorption spectrum of lymph nodes. Usingillumination light between 800-1700 nm in wavelength, and especially1550 nm in wavelength, the imaging system generates images showing lymphnodes that naturally stand out from their surrounding tissues includingfat, blood, and/or hemorrhages as described above. Image contrast oflymph nodes can be improved by the implementation of polarizers;however, they are not necessary for the method. This disclosure providessystems and methods to visualize lymph nodes noninvasively and canbecome a powerful tool for health screening, disease prevention,diagnosis, and treatment.

Certain embodiments of imaging systems provided by the disclosure canalso be economically constructed. For example, embodiments similar tothe imaging system 200 of FIG. 2 may cost less than 100 dollars tobuild. Thus, certain lymph node imaging systems can be constructed farmore affordably than any of the cross-sectional imaging modalities. CT,MM, Ultrasound and PET instruments cost from tens of thousands of USdollars to millions of US dollars. The affordability of these providedimaging systems will help make a far larger impact in clinical settings.These imaging systems can be potentially used by medical practitionersor even regular consumers to conduct routine health checks, trackdisease reoccurrence, etc. Also, unlike the cross-sectional modalities,the wavelength range of the disclosed imaging systems are specific tonatural lymph nodes and lymphatic vessels, (i.e. lymph nodes andlymphatic vessels without any external injections). Even imaging systemsthat include relatively more expensive components (e.g., an InGaAscamera used as the sensor) may still be constructed more economicallythan at least some of the cross-sectional modalities mentioned above.

It should be understood that the above described steps of the processesof FIG. 6 can be executed or performed in an order or sequence notlimited to the order and sequence shown and described in the figures.Also, some of the above steps of the processes of FIGS. 5 and 6 can beexecuted or performed substantially simultaneously where appropriate orin parallel to reduce latency and processing times.

In some embodiments, aspects of the present disclosure, includingcomputerized implementations of methods, can be implemented as a system,method, apparatus, or article of manufacture using standard programmingor engineering techniques to produce software, which can be firmware,hardware, or any combination thereof to control a processor device, acomputer (e.g., a processor device operatively coupled to a memory), oranother electronically operated controller to implement aspects detailedherein. Accordingly, for example, embodiments of the invention can beimplemented as a set of instructions, tangibly embodied on anon-transitory computer-readable media, such that a processor device canimplement the instructions based upon reading the instructions from thecomputer-readable media. Some embodiments of the invention can include(or utilize) a device such as an automation device, a special purpose orgeneral purpose computer including various computer hardware, software,firmware, and so on, consistent with the discussion below.

The term “article of manufacture” as used herein is intended toencompass a computer program accessible from any computer-readabledevice, carrier (e.g., non-transitory signals), or media (e.g.,non-transitory media). For example, computer-readable media can includebut can be not limited to magnetic storage devices (e.g., hard disk,floppy disk, magnetic strips, and so on), optical disks (e.g., compactdisk (CD), digital versatile disk (DVD), and so on), smart cards, andflash memory devices (e.g., card, stick, and so on). Additionally, itshould be appreciated that a carrier wave can be employed to carrycomputer-readable electronic data such as those used in transmitting andreceiving electronic mail or in accessing a network such as the Internetor a local area network (LAN). Those skilled in the art will recognizemany modifications may be made to these configurations without departingfrom the scope or spirit of the claimed subject matter.

Certain operations of methods according to the invention, or of systemsexecuting those methods, may be represented schematically in the Figuresor otherwise discussed herein. Unless otherwise specified or limited,representation in the Figures of particular operations in particularspatial order may not necessarily require those operations to beexecuted in a particular sequence corresponding to the particularspatial order. Correspondingly, certain operations represented in theFigures, or otherwise disclosed herein, can be executed in differentorders than can be expressly illustrated or described, as appropriatefor particular embodiments of the invention. Further, in someembodiments, certain operations can be executed in parallel, includingby dedicated parallel processing devices, or separate computing devicesconfigured to interoperate as part of a large system.

As used herein in the context of computer implementation, unlessotherwise specified or limited, the terms “component,” “system,”“module,” etc. can be intended to encompass part or all ofcomputer-related systems that include hardware, software, a combinationof hardware and software, or software in execution. For example, acomponent may be, but is not limited to being, a processor device, aprocess being executed (or executable) by a processor device, an object,an executable, a thread of execution, a computer program, or a computer.By way of illustration, both an application running on a computer andthe computer can be a component. One or more components (or system,module, and so on) may reside within a process or thread of execution,may be localized on one computer, may be distributed between two or morecomputers or other processor devices, or may be included within anothercomponent (or system, module, and so on).

As used herein, the term, “controller” and “processor” include anydevice capable of executing a computer program, or any device that caninclude logic gates configured to execute the described functionality.For example, this may include a processor, a microcontroller, afield-programmable gate array, a programmable logic controller, etc.

The discussion herein is presented for a person skilled in the art tomake and use embodiments of the invention. Various modifications to theillustrated embodiments will be readily apparent to those skilled in theart, and the generic principles herein can be applied to otherembodiments and applications without departing from embodiments of theinvention. Thus, embodiments of the invention can be not intended to belimited to embodiments shown, but can be to be accorded the widest scopeconsistent with the principles and features disclosed herein. Thedetailed description is to be read with reference to the figures, inwhich like elements in different figures have like reference numerals.The figures, which can be not necessarily to scale, depict selectedembodiments and can be not intended to limit the scope of embodiments ofthe invention. Skilled artisans will recognize the examples providedherein have many useful alternatives and fall within the scope ofembodiments of the invention.

Thus, as described above, systems and methods are provided to visualizelymphatic components with near-infrared (800-1400 nm) and/ or short-waveinfrared (1400-3000 nm). For example, illumination between 800-1700 nmmay be used. For some applications, an illumination wavelength between1500-1600 nm such as 1550 nm may beneficial for imaging lymphaticcomponents. In one embodiment, only 1550 nm wavelength illumination maybe used.

The systems and methods described herein provide near-infrared and/orshort-infrared imaging techniques that use one or multiple near-infraredor short-wave infrared light sources and sensors. The imaging system canwork together with polarizers. A polarizer can be placed in front of thelight source(s), which may also be referred to as optical source(s), andanother polarizer can be placed in front of the sensor(s). Therotational angle of between two polarizers can be adjusted to minimizedirect reflection off the skin of a human or animal and optimize thevisualization of lymphatic components. In some configurations, the useof a polarizer in front of the light source(s) can be unnecessary, andthe imaging system can function without the polarizer positioned infront of the light source(s). Some light sources emit linearly polarizedlight due to its inherent working mechanism without a polarizer. Thus,polarizers are helpful for improving the contrast of lymphaticcomponents; however, they are not necessary. Lymphatic components canstill be visualized without any polarizers or polarizationmodifications, particularly when the illumination wavelength is between800-1700 nm, and the sensor is ready to detect light in this wavelengthrange.

In one aspect, the present disclosure provides a lymphatic componentimaging system. The system includes an optical source configured toprovide infrared illumination to a region of a subject having at leastone lymphatic component, a sensor configured to sense a reflectedportion of the infrared illumination directly reflected from the region,and a controller in communication with the optical source and the sensorand configured to cause the optical source to provide the infraredillumination to the region, receive, from the sensor, informationcorresponding to the reflected portion of the infrared illumination, andgenerate at least one image indicative of the at least one lymphaticcomponent in the subject using the information.

The system may be configured to generate the at least one imageindicative of the at least one lymphatic component without referencelight. The system may be configured to generate the at least one imageindicative of the at least one lymphatic component without informationfrom ambient light surrounding the sensor. In the system, the opticalsource may include a laser. In the system, the optical source mayinclude a light emitting diode. The system may further include alongpass or bandpass filter arranged between the region and the opticalsource and having with a cutoff wavelength of no less than 800 nm. Inthe system, the sensor may include at least one of a silicon camera, anInGaAs camera, and a black silicon camera. The system may furtherinclude a polarizer arranged between the region and the sensor. Thesystem may not include a contrast agent and the at least one lymphaticcomponent may include a lymph node or a lymphatic vessel. In the system,the infrared illumination may have an illumination wavelength of800-1700 nm.

In another aspect, the present disclosure provides a method for imaginglymphatic components without a contrast agent. The method includesproviding, using an optical source, an infrared illumination to an invivo region of a subject having lymphatic components, detecting areflected portion of the infrared illumination directly reflected fromthe region using a sensor positioned thereabout, and generating at leastone image indicative of the lymphatic components in the subject usingthe reflected portion of the infrared illumination.

In the method, the infrared illumination may have an illuminationwavelength of 800-2000 nm. In the method, the infrared illumination maybe provided without use of a polarizer. The method may further includerotating a polarizer in front of the sensor until a lowest overallintensity is detected by the sensor. In the method, the infraredillumination may have an optical power of no more than 1 mW. The methodmay further include positioning a polarizer between the region and thesensor, and arranging the polarizer to be approximately orthogonal tothe infrared illumination directly reflected from the region. The methodmay further include adjusting at least one of the polarizer and thelight source until a threshold contrast level is achieved at the sensor.

In yet another aspect, the present disclosure provides a method forimaging lymphatic components without a mirror. The method includesproviding, using an optical source, an infrared illumination to a regionof a subject having lymphatic components, detecting a reflected portionof the infrared illumination directly reflected from the region using asensor positioned thereabout, and generating at least one imageindicative of the lymphatic components in the subject using thereflected portion of the infrared illumination. In the method, theinfrared illumination may have an illumination wavelength of 800-2000nm. In the method, the infrared illumination may be provided without useof a polarizer.

Although the invention has been described in considerable detail withreference to certain embodiments, one skilled in the art will appreciatethat the present invention can be practiced by other than the describedembodiments, which have been presented for purposes of illustration andnot of limitation. Therefore, the scope of the appended claims shouldnot be limited to the description of the embodiments contained herein.

1-26. (canceled)
 27. A method for imaging biological tissue, the methodcomprising: providing infrared illumination, by an optical source, to aregion of a subject having biological tissue comprising a first tissueregion and a second tissue region, wherein the first tissue region has afirst water content level and the second tissue region has a secondwater content level that is lower than the first water content level,wherein the infrared illumination has an illumination wavelength of1000-2600 nm; sensing, by a sensor, a first reflected portion of theinfrared illumination and a second reflected portion of the infraredillumination, wherein the first reflected portion of the infraredillumination is reflected from the first tissue region and has a firstintensity, and wherein the second reflected portion of the infraredillumination is reflected from the second tissue region and has a secondintensity that is higher than the first intensity; and receiving, by acontroller in communication with the sensor, from the sensor,information corresponding to the first reflected portion of the infraredillumination and the second reflected portion of the infraredillumination; generating, by the controller, at least one image of theat least one biological tissue in the subject using the information,wherein the at least one image distinguishes the first tissue regionfrom the second tissue region; and outputting, by the controller, the atleast one image to at least one of a display and/or a memory.
 28. Themethod of claim 27, wherein the at least one image is generated withoutreference light.
 29. The method of claim 27, wherein the at least oneimage is generated without information from ambient light surroundingthe sensor.
 30. The method of claim 27, wherein the optical sourceincludes a laser.
 31. The method of claim 27, wherein the optical sourceincludes a light emitting diode.
 32. The method of claim 27, furthercomprising filtering the infrared illumination, by a longpass orbandpass filter arranged between the region and the optical source,wherein the longpass or bandpass filter has a cutoff wavelength of noless than 800 nm.
 33. The method of claim 27, wherein the sensorincludes at least one of a silicon camera, an InGaAs camera, or a blacksilicon camera.
 34. The method of claim 27, wherein the sensor includesat least one of a germanium camera, a germanium-tin on silicon camera, aquantum dot shortwave infrared camera, or a mercury-cadmium-telluridecamera.
 35. The method of claim 27, further comprising polarizing theinfrared illumination, by a first polarizer, such that the infraredillumination incident on the biological tissue has a first polarization.36. The method of claim 35, further comprising polarizing the firstreflected portion of the infrared illumination and the second reflectedportion of the infrared illumination, by a second polarizer, such thatthe first reflected portion of the infrared illumination and the secondreflected portion of the infrared illumination incident on the sensorhave a second polarization that is opposite the first polarization. 37.The method of claim 27, wherein the biological tissue is free of acontrast agent.
 38. The method of claim 27, wherein the first tissueregion comprises lymphatic tissue and the second tissue region comprisesfat tissue.
 39. The method of claim 27, wherein the first tissue regionhas a first absorption at 1550 nm, and the second tissue region has asecond absorption at 1550 nm, wherein the first absorption is higherthan the second absorption.
 40. The method of claim 27, wherein theinfrared illumination has an illumination wavelength of 1000-1700 nm.41. The method of claim 27, wherein the infrared illumination has anillumination wavelength of 1500-1700 nm.
 42. The method of claim 1,wherein the infrared illumination has an illumination wavelength of 1300nm.
 43. The method of claim 27, wherein the infrared illumination has anoptical power of no more than 1 mW.
 44. A system for imaging biologicaltissue, the system comprising: an optical source configured to provideinfrared illumination to a region of a subject having biological tissuecomprising a first tissue region and a second tissue region, wherein thefirst tissue region has a first water content level and the secondtissue region has a second water content level that is lower than thefirst water content level, wherein the infrared illumination has anillumination wavelength of 1000-2600 nm; a sensor configured to sense afirst reflected portion of the infrared illumination and a secondreflected portion of the infrared illumination, wherein the firstreflected portion of the infrared illumination is reflected from thefirst tissue region and has a first intensity, and wherein the secondreflected portion of the infrared illumination is reflected from thesecond tissue region and has a second intensity that is higher than thefirst intensity; and a controller in communication with the sensor andconfigured to: receive, from the sensor, information corresponding tothe first reflected portion of the infrared illumination and the secondreflected portion of the infrared illumination; generate at least oneimage of the at least one biological tissue in the subject using theinformation, wherein the at least one image distinguishes the firsttissue region from the second tissue region; and output the at least oneimage to at least one of a display and/or a memory.
 45. The system ofclaim 44, further comprising a first polarizer arranged between theoptical source and the biological tissue and configured to polarize theinfrared illumination such that the infrared illumination incident onthe biological tissue has a first polarization.
 46. The system of claim45, further comprising a second polarizer arranged between thebiological tissue and the sensor and configured to polarize the firstreflected portion of the infrared illumination and the second reflectedportion of the infrared illumination, such that the first reflectedportion of the infrared illumination and the second reflected portion ofthe infrared illumination incident on the sensor have a secondpolarization that is opposite the first polarization.